Neurologic Recovery in MPS I and MPS II Mice by AAV9-Mediated Gene Transfer to the CNS After the Development of Cognitive Dysfunction

Podetz-Pedersen, Kelly M.; Laoharawee, Kanut; Singh, Siddharth; Nguyen, Tam T. T. N.; Smith, Miles; Temme, Alexa; Kozarsky, Karen; Ivor, R S Mc; Belur, Lalitha R.

doi:10.1089/hum.2022.162

Cited by 3 publications

(2 citation statements)

References 58 publications

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“…On the other hand, similar reductions in brain HS and lysosomal swelling, and cerebellar function normalisation were observed following both treatments. This is in line with the neurologic recovery observed in both MPS I and MPS II mice when treated at advanced disease stages with AAV9 vector administered intracerebroventricularly and intravenously 28,29 . There are many possible reasons for the decrease in CNS enzyme expression.…”

Section: Human Gene Therapysupporting

confidence: 84%

Establishment of the Effectiveness of Early Versus Late Stem Cell Gene Therapy in Mucopolysaccharidosis II for Treating Central Versus Peripheral Disease

et al. 2024

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Section: Human Gene Therapysupporting

confidence: 84%

Establishment of the Effectiveness of Early Versus Late Stem Cell Gene Therapy in Mucopolysaccharidosis II for Treating Central Versus Peripheral Disease

et al. 2024

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“…Finally, Barnes Maze assays were utilized to evaluate the spatial learning and cognition of the Tm-treated mice to assess the neurocognitive benefits of our treatment. 42–44 We noted a subtle cognitive enhancement in the Tm-treated mice, suggesting a potential trend toward neurocognitive improvement. Despite this modest outcome, it’s noteworthy that human IDUA activity was detected across all measured tissues.…”

Section: Discussionmentioning

confidence: 84%

Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders

Laoharawee,

Kleinboehl,

Jensen

et al. 2024

Preprint

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Enzymopathy disorders are the result of missing or defective enzymes. Amongst these enzymopathies, mucopolysaccharidosis type I, is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), ultimately causes toxic build-up of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T cells (Tm) migrate throughout the body's tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS. Our study indicates that genetically engineered Tm holds great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.

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Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II

Smith

Belur

Karlen

et al. 2023

Molecular Genetics and Metabolism

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Neurologic Recovery in MPS I and MPS II Mice by AAV9-Mediated Gene Transfer to the CNS After the Development of Cognitive Dysfunction

Cited by 3 publications

References 58 publications

Establishment of the Effectiveness of Early Versus Late Stem Cell Gene Therapy in Mucopolysaccharidosis II for Treating Central Versus Peripheral Disease

Establishment of the Effectiveness of Early Versus Late Stem Cell Gene Therapy in Mucopolysaccharidosis II for Treating Central Versus Peripheral Disease

Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders

Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II

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